ABSTRACT Two primary clinical deficits associated with Spinal Cord Injury (SCI) are spastic muscle hypertonia and impaired voluntary control of movement. Hypertonia, defined as an abnormal increase in muscle tone, is a defining feature of spasticity and has both diagnostic and therapeutic significance. Hypertonia arises from abnormalities in mechanical properties of muscles, passive tissues, and reflexes. Various physical and pharmacological treatments have been proposed to decrease hypertonia and to improve function. However, the effects of such interventions have not been quantified, primarily due to a lack of quantitative tools that can separate and characterize these components. To address this deficit, we have developed a parallel cascade system identification model that can be used to characterize joint dynamic stiffness and separate its muscular and reflexive components. The overall goal of this study is to predict the effects of therapeutic interventions on functional recovery. We plan two interventions; a pharmacological intervention (tizanidine, the -2 noradrenergic agonist), and a physical intervention (robotic locomotor training [LOKOMAT]). Although tizanidine has been used to treat spasticity, and the LOKOMAT to improve locomotion, there have been no prior attempts to characterize the interactions between these therapies. The focus of this study will be on the mechanisms of action of these interventions in SCI. Therefore, we plan to quantify the effects of these interventions on neuromechanical abnormalities associated with spasticity and on impaired voluntary movement and functional impairment, in addition to determining the relationship between these two. Aim 1 is to determine the effect of tizanidine and the LOKOMAT on voluntary and reflexive motor behavior by using the parallel system identification technique to characterize the impact of these interventions on reflex and mechanical properties associated with spasticity. We hypothesize that tizanidine and the LOKOMAT will each modify reflex function and muscle mechanics; however, combining these techniques will improve outcomes over each intervention separately. Aim 2 is to quantify the effects of these treatments on impaired voluntary movement. We hypothesize that tizanidine will improve active range of motion, movement smoothness and movement time. The LOKOMAT will improve maximum speed, active range of motion and movement time. Furthermore, combined tizanidine and LOKOMAT will improve all these movement parameters to a disproportionate extent. Aim 3 is to quantify the effects of these treatments on clinical measure of impairments and functional limitations. We hypothesize that tizanidine will improve, muscle strength, gait endurance and volitional control. The LOKOMAT will improve passive range of motion, muscle strength, gait speed and endurance, balance, and ambulation. We expect to see even greater improvements when the two interventions are combined. Aim 4 is to determine the contributions of changes in neuromuscular properties to improvement in impaired voluntary movement, clinical impairments and functional impairments. The results will document the role of each mechanical abnormality in functional impairments for each treatment. We hypothesize that the reduced reflex stiffness, as well as the modified muscle mechanics, will be related with improvement of the movement parameters, gait endurance and speed, volitional control, and ambulation. Our results will provide the information needed to develop accurate, quantitative models, capable of distinguishing changes in muscular system from changes in neural pathways in neurological disorders such as SCI. We should also be able to analyze their contributions to functional impairment. Improved understanding of the role of muscular and reflexive abnormalities in impaired movements, combined with accurate assessment techniques, will enable us to predict the outcome of various clinical interventions, and consequently to prescribe optimal treatment for spasticity and impaired walking.